Targeting programmed cell death in metabolic dysfunction-associated fatty liver disease (MAFLD): a promising new therapy.
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ABSTRACT:
SUBMITTER: Zhao J
PROVIDER: S-EPMC8103580 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new term from nonalcoholic fatty liver disease (NAFLD) and is a positive diagnosis based on histopathology, imaging, or blood biomarkers. MAFLD is one of the common causes of liver dysfunction worldwide, likely due to the increase in metabolic syndrome as well as the high burden of disease and its relationship to other extrahepatic conditions. However, effective pharmacological therapeutic agents are still lacking; current management largely focuses on weight reduction and lifestyle modification. The purpose of this review was to summarize the updated evidence of novel therapies targeting different pathogenetic pathways in MAFLD.
| S-EPMC8666366 | biostudies-literature
Project description:Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease affecting a quarter of the global population and is often associated with adverse health outcomes. The increasing prevalence of MAFLD occurs in parallel to that of metabolic syndrome (MetS), which in fact plays a major role in driving the perturbations of cardiometabolic homeostasis. However, the mechanisms underpinning the pathogenesis of MAFLD are incompletely understood. Compelling evidence from animal and human studies suggest that heightened activation of the sympathetic nervous system is a key contributor to the development of MAFLD. Indeed, common treatment strategies for metabolic diseases such as diet and exercise to induce weight loss have been shown to exert their beneficial effects at least in part through the associated sympathetic inhibition. Furthermore, pharmacological and device-based approaches to reduce sympathetic activation have been demonstrated to improve the metabolic alterations frequently present in patients with obesity, MetSand diabetes. Currently available evidence, while still limited, suggests that sympathetic activation is of specific relevance in the pathogenesis of MAFLD and consequentially may offer an attractive therapeutic target to attenuate the adverse outcomes associated with MAFLD.
| S-EPMC8073135 | biostudies-literature
Project description:BackgroundSome studies found that red blood cell count (RBC) was an unrecognized risk factor for non-alcoholic fatty liver disease (NAFLD). While the epidemiological data underpinning the evidence is very limited. As there are some differences between the latest criteria of metabolic dysfunction-associated fatty liver disease (MAFLD) and NAFLD, itis necessary to evaluate the relationship between RBC and MAFLD.MethodsWe performed a cross-sectional analysis of the National Health and Nutritional Examination Survey (NHANES)2017-2018 cohort, including 4477 participants. Hepatic steatosis was determined when the value of controlled attenuation parameter (CAP) obtained by Fibroscan was ≥274 dB/m. Multivariate logistic regression analysis was used to estimate the association between RBC and MAFLD. We estimated the adjusted odds ratio (OR) of RBC for MAFLD, and the nonlinear relationship between RBC and MAFLD was further described using smooth curve fittings and threshold-effect analysis.ResultsWe found that MAFLD risk was significantly higher according to RBC quartiles. The adjusted odds ratio (OR) and 95% confidence intervals (CIs)for the highest RBC quartile were 1.5(1.0, 2.3) for male and 1.1 (0.8, 1.6) for female, respectively. As for male, a non-linear relationship was discovered between RBCs and MAFLD, with a RBC threshold of 4.2. The effect sizes and confidence intervals on the right side of the inflection point were 1.5 (1.0, 2.0) (P for nonlinearity = 0.027). The sensitivity analysis showed a similar result.ConclusionWe demonstrated that that elevated RBC level is associated with the higher risk of MAFLD in male. The positive relationship was not significant in females after full adjustment. Our finding provided novel evidence indicating that RBCs might be a potential biomarker for MAFLD.
| S-EPMC9794081 | biostudies-literature
Project description:In the past decade, G protein-coupled receptors have emerged as drug targets, and their physiological and pathological effects have been extensively studied. Among these receptors, GPR119 is expressed in multiple organs, including the liver. It can be activated by a variety of endogenous and exogenous ligands. After GPR119 is activated, the cell secretes a variety of incretins, including glucagon-like peptide-1 and glucagon-like peptide-2, which may attenuate the metabolic dysfunction associated with fatty liver disease, including improving glucose and lipid metabolism, inhibiting inflammation, reducing appetite, and regulating the intestinal microbial system. GPR119 has been a potential therapeutic target for diabetes mellitus type 2 for many years, but its role in metabolic dysfunction associated fatty liver disease deserves further attention. In this review, we discuss relevant research and current progress in the physiology and pharmacology of the GPR119/incretin axis and speculate on the potential therapeutic role of this axis in metabolic dysfunction associated with fatty liver disease, which provides guidance for transforming experimental research into clinical applications.
| S-EPMC8265056 | biostudies-literature
Project description:Metabolic dysfunction-associated fatty liver disease (MAFLD) is nowadays considered the liver manifestation of metabolic syndrome. Its prevalence is increasing worldwide in parallel to the epidemic of diabetes and obesity. MAFLD includes a wide spectrum of liver injury including simple steatosis and non-alcoholic steatohepatitis (NASH) that may lead to serious complications such as liver cirrhosis and liver cancer. The complexity of its pathophysiology and the intricate mechanisms underlying disease progression explains the huge variety of molecules targeting diverse biological mechanisms that have been tested in preclinical and clinical settings in the last two decades. Thanks to the large number of clinical trials of the last few years, most of them still ongoing, the pharmacotherapy scenario of MAFLD is rapidly evolving. The three major components of MAFLD, steatosis, inflammation, and fibrosis seem to be safely targeted with different agents at least in a large proportion of patients. Likely, in the next few years more than one drug will be approved for the treatment of MAFLD at different disease stages. The aim of this review is to synthesize the characteristics and the results of the most advanced clinical trials for the treatment of NASH to evaluate the recent advances of pharmacotherapy in this disease.
| S-EPMC10635944 | biostudies-literature
Project description:Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC. alb-myctg mice were studied at baseline conditions and after administration of Western diet (WD) in comparison to WT littermates. c-MYC expression was analyzed in biopsies of patients with MAFLD and MAFLD-associated HCC by immunohistochemistry. Mild obesity, spontaneous hyperlipidaemia, glucose intolerance and insulin resistance were characteristic of 36-week-old alb-myctg mice. Middle-aged alb-myctg exhibited liver steatosis and increased triglyceride content. Liver injury and inflammation were associated with elevated ALT, an upregulation of ER-stress response and increased ROS production, collagen deposition and compensatory proliferation. At 52 weeks, 20% of transgenic mice developed HCC. WD feeding exacerbated metabolic abnormalities, steatohepatitis, fibrogenesis and tumor prevalence. Therapeutic use of metformin partly attenuated the spontaneous MAFLD phenotype of alb-myctg mice. Importantly, upregulation and nuclear localization of c-MYC were characteristic of patients with MAFLD and MAFLD-related HCC. A novel function of c-MYC in MAFLD progression was identified opening new avenues for preventative strategies.
| S-EPMC8750626 | biostudies-literature
Project description:Individuals with metabolic dysfunction-associated fatty liver disease (MAFLD) have elevated plasma lipids as well as glucagon, although glucagon suppresses hepatic VLDL-triglyceride (TG) secretion. We hypothesize that the sensitivity to glucagon in hepatic lipid metabolism is impaired in MAFLD. We recruited 11 subjects with severe MAFLD (MAFLD+), 10 with mild MAFLD (MAFLD-), and 7 overweight control (CON) subjects. We performed a pancreatic clamp with a somatostatin analog (octreotide) to suppress endogenous hormone production, combined with infusion of low-dose glucagon (0.65 ng/kg/min, t = 0-270 min, LowGlucagon), followed by high-dose glucagon (1.5 ng/kg/min, t = 270-450 min, HighGlucagon). VLDL-TG and glucose tracers were used to evaluate VLDL-TG kinetics and endogenous glucose production (EGP). HighGlucagon suppressed VLDL-TG secretion compared with LowGlucagon. This suppression was markedly attenuated in MAFLD subjects compared with CON subjects (MAFLD+: 13% ± [SEM] 5%; MAFLD-: 10% ± 3%; CON: 36% ± 7%, P < 0.01), with no difference between MAFLD groups. VLDL-TG concentration and VLDL-TG oxidation rate increased between LowGlucagon and HighGlucagon in MAFLD+ subjects compared with CON subjects. EGP transiently increased during HighGlucagon without any difference between the three groups. Individuals with MAFLD have a reduced sensitivity to glucagon in the hepatic TG metabolism, which could contribute to the dyslipidemia seen in MAFLD patients. ClinicalTrials.gov: NCT04042142.
| S-EPMC9630084 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) has recently become the most common liver disease with a global prevalence of over 25% and is expected to increase. Recently, experts have reached a consensus that "fatty liver disease associated with metabolic dysfunction or MAFLD" may be a more appropriate and inclusive definition than NAFLD. Like the former name NAFLD, MAFLD, as a manifestation of multiple system metabolic disorders involving the liver, has certain heterogeneity in its pathogenesis, clinical manifestations, pathological changes and natural outcomes. We found that there is a delicate dynamic balance among intestinal microflora, metabolites and host immune system to maintain a healthy intestinal environment and host health. On the contrary, this imbalance is related to diseases such as MAFLD. However, there are no clear studies on how dietary nutrients affect the intestinal environment and participate in the pathogenesis of MAFLD. This review summarizes the interactions among dietary nutrients, intestinal microbiota and MAFLD in an attempt to provide evidence for the use of dietary supplements to regulate liver function in patients with MAFLD. These dietary nutrients influence the development and progression of MAFLD mainly through the hepatic-intestinal axis by altering dietary energy absorption, regulating bile acid metabolism, changing intestinal permeability and producing ethanol. Meanwhile, the nutrients have the ability to combat MAFLD in terms of enriching abundance of intestinal microbiota, reducing Firmicutes/Bacteroidetes ratio and promoting abundance of beneficial gut microbes. Therefore, family therapy with MAFLD using a reasonable diet could be considered.
| S-EPMC9247350 | biostudies-literature
Project description:BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) is one of the most prevalent metabolic syndromes worldwide. However, no approved pharmacological treatments are available for MAFLD. Chenpi, one kind of dried peel of citrus fruits, has traditionally been utilized as a medicinal herb for liver diseases. Didymin is a newly identified oral bioactive dietary flavonoid glycoside derived from Chenpi. In this study, we investigated the therapeutic potential of Didymin as an anti-MAFLD drug and elucidated its underlying mechanisms.MethodsHigh-fat diet (HFD)-induced MAFLD mice and alpha mouse liver 12 (AML12) cells were utilized to evaluate the effects and mechanisms of Didymin in the treatment of MAFLD. Liver weight, serum biochemical parameters, and liver morphology were examined to demonstrate the therapeutic efficacy of Didymin in MAFLD treatment. RNA-seq analysis was performed to identify potential pathways that could be affected by Didymin. The impact of Didymin on Sirt1 was corroborated through western blot, molecular docking analysis, microscale thermophoresis (MST), and deacetylase activity assay. Then, a Sirt1 inhibitor (EX-527) was utilized to confirm that Didymin alleviates MAFLD via Sirt1. Western blot and additional assays were used to investigate the underlying mechanisms.ResultsOur results suggested that Didymin may possess therapeutic potential against MAFLD in vitro and in vivo. By promoting Sirt1 expression as well as directly binding to and activating Sirt1, Didymin triggers downstream pathways that enhance mitochondrial biogenesis and function while reducing apoptosis and enhancing lipophagy.ConclusionsThese suggest that Didymin could be a promising medication for MAFLD treatment. Furthermore, its therapeutic effects are mediated by Sirt1.
| S-EPMC10731721 | biostudies-literature
Project description:Hepatic steatosis signifies onset of metabolic dysfunction-associated fatty liver disease (MAFLD) caused by disrupted metabolic homeostasis compromising liver function. Regular consumption of common beans reduces the risk of metabolic impairment, but its effective dose, the impact of biological sex, and underlying mechanisms of action are unknown. We fed female and male C57BL6/J mice with obesogenic yet isocaloric diets containing 0%, 17.5%, 35%, and 70% of total dietary protein derived from cooked whole common beans. Liver tissue was collected for histopathology, lipid quantification, and RNA-seq analyses. Beans qualitatively and quantitatively diminished hepatic fat deposition at the 35% dose in female and 70% dose in male mice. Bean-induced differentially expressed genes (DEGs) most significantly mapped to hepatic steatosis and revealed dose-responsive inhibition of de novo lipogenesis markers (Acly, Acaca, Fasn, Elovl6, Scd1, etc.) and triacylglycerol biosynthesis, activation of triacylglycerol degradation, and downregulation of sterol regulatory element-binding transcription factor 1 (SREBF1) signaling. Upregulated fatty acid β-oxidation was more prominent in females, while suppression of Cd36-mediated fatty acid uptake—in males. Sex-dependent bean effects also involved DEGs patterns downstream of peroxisome proliferator-activated receptor α (PPARα) and MLX-interacting protein-like (MLXIPL). Therefore, biological sex determines amount of common bean in the diet required to prevent hepatic lipid accumulation.
| S-EPMC9920904 | biostudies-literature